The present invention is generally in the area of polymeric drug delivery devices.
Controlled release systems for drug delivery are often designed to administer drugs in specific areas of the body. In the case of drug delivery via the gastrointestinal tract, it is critical that the drug not be entrained beyond the desired site of action and eliminated before it has had a chance to exert a topical effect or to pass into the bloodstream. If a drug delivery system can be made to adhere to the lining of the appropriate viscus, its contents will be delivered to the targeted tissue as a function of proximity and duration of the contact.
An orally ingested product can adhere to either the epithelial surface or the mucus. For the delivery of bioactive substances, it can be advantageous to have a polymeric drug delivery device adhere to the epithelium or to the mucous layer. Bioadhesion in the gastrointestinal tract proceeds in two stages: (1) viscoelastic deformation at the point of contact of the synthetic material into the mucus substrate, and (2) formation of bonds between the adhesive synthetic material and the mucus or the epithelial cells. In general, adhesion of polymers to tissues may be achieved by (i) physical or mechanical bonds, (ii) primary or covalent chemical bonds, and/or (iii) secondary chemical bonds (i.e., ionic). Physical or mechanical bonds can result from deposition and inclusion of the adhesive material in the crevices of the mucus or the folds of the mucosa. Secondary chemical bonds, contributing to bioadhesive properties, consist of dispersive interactions (i.e., Van der Waals interactions) and stronger specific interactions, which include hydrogen bonds. The hydrophilic functional groups primarily responsible for forming hydrogen bonds are the hydroxyl and the carboxylic groups.
Several microsphere formulations have been proposed as a means for oral drug delivery. These formulations generally serve to protect the encapsulated compound and to deliver the compound into the blood stream. Enteric coated formulations have been widely used for many years to protect drugs administered orally, as well as to delay release. Other formulations designed to deliver compounds into the blood stream, as well as to protect the encapsulated drug, are formed of a hydrophobic protein, such as zein, as described in PCT/US90/06430 and PCT/US90/06433; xe2x80x9cproteinoidsxe2x80x9d, as described in U.S. Pat. No. 4,976,968 to Steiner; or synthetic polymers, as described in European Patent application 0 333 523 by The UAB Research Foundation and Southern Research Institute. EPA 0 333 523 describes microparticles of less than ten microns in diameter that contain antigens, for use in oral administration of vaccines. The microparticles are formed of polymers such as poly(lactide-co-glycolide), poly(glycolide), polyorthoesters, poly(esteramides), polyhydroxybutyric acid and polyanhydrides, and are absorbed through the Peyer""s Patches in the intestine, principally as a function of size.
Duchene et al., Drug Dev. Ind Pharm., 14, 283-318 (1988) is a review of the pharmaceutical and medical aspects of bioadhesive systems for drug delivery. Polycarbophils and acrylic acid polymers were noted as having the best adhesive properties. xe2x80x9cBioadhesionxe2x80x9d is defined as the ability of a material to adhere to a biological tissue for an extended period of time. Bioadhesion is clearly one solution to the problem of inadequate residence time resulting from the stomach emptying and intestinal peristalsis, and from displacement by cilliary movement. For sufficient bioadhesion to occur, an intimate contact must exist between the bioadhesive and the receptor tissue, the bioadhesive must penetrate into the crevice of the tissue surface and/or mucus, and mechanical, electrostatic, or chemical bonds must form. Bioadhesive properties of polymers are affected by both the nature of the polymer and by the nature of the surrounding media.
Others have explored the use of bioadhesive polymers. PCT WO 93/21906 discloses methods for fabricating bioadhesive microspheres and for measuring bioadhesive forces between microspheres and selected segments of the gastrointestinal tract in vitro. Smart et al., J. Pharm. Pharmacol, 36:295-99 (1984), reported a method to test adhesion to mucosa using a polymer coated glass plate contacting a dish of mucosa. A variety of polymeric materials were tested, including sodium alginate, sodium carboxymethyl-cellulose, gelatin, pectin and polyvinylpyrrolidone. Gurney et al., Biomaterials, 5:336-40 (1984) reported that adhesion may be effected by physical or mechanical bonds; secondary chemical bonds; and/or primary, ionic or covalent bonds. Park et al., xe2x80x9cAlternative Approaches to Oral Controlled Drug Delivery: Bioadhesives and In-Situ Systems,xe2x80x9d in Anderson and Kim, eds., xe2x80x9cRecent Advances in Drug Delivery,xe2x80x9d pp. 163-83, (Plenum Press, New York 1984) reported a study of the use of fluorescent probes in cells to determine adhesiveness of polymers to mucin/epithelial surface, which indicated that anionic polymers with high charge density appear to be preferred as adhesive polymers.
Mikos etal., in J. Colloid Interface Sci., 143:366-73 (1991) and Lehr et al., J. Controlled Rel. Soc., 13;51-62 (1990) reported a study of the bioadhesive properties of polyanhydrides and polyacrylic acid, respectively, in drug delivery. Lehr et al. screened microparticles formed of copolymers of acrylic acid using an in vitro system and determined that the copolymer xe2x80x9cPolycarbophilxe2x80x9d has increased adhesion.
In general, gastrointestinal (GI) mucus is made of 95% water and 5% electrolytes, lipids, proteins and glycoproteins, as described by Spiro, Annual Review of Biochemistry, 39:599-638 (1970); and Labat-Robert and Decaeus, Pathologie et Biologie (Paris), 24:241 (1979). However, the composition of the latter fraction can vary greatly. Proteins, including the protein core of the glycoproteins, can make up anywhere from 60 to 80% of this fraction. Horowitz, xe2x80x9cMucopolysaccharides and Glycoproteins of the Alimentary Tractxe2x80x9d in Alimentary Canal (eds. C. F. Code), pp. 1063-85 (Washington: American Physiological Society, 1967). The glycoproteins typically have a molecular weight of approximately two million and consist of a protein core (approximately 18.6-25.6% by weight) with covalently attached carbohydrate side chains (approximately 81.4-74.4% by weight) terminating in either L-fucose or sialic acid residues. Spiro, Annual Review of Biochemistry, 39:599-638 (1970); Scawen and Allen, xe2x80x9cThe Action of Proteolytic Enzymes on the Glycoprotein from Pig Gastric Mucus,xe2x80x9d Biochemical J., 163:363-68 (1977); Horowitz and Pigman, The Glycoconjugates, pp. 560 (New York: Academic Press, Inc., 1977); Pigman and Gottschalk, xe2x80x9cSubmaxillary Gland Glycoproteinsxe2x80x9d in Glycoproteins: Their Composition, Structure and Function (eds. A. Gottschalk), pp. 434-45 (Amsterdam: Elsevier Publishing Company, Inc., 1966). Species and location differences in the composition of these glycoproteins have been reported by Horowitz in Alimentary Canal (eds. C. F. Code), pp. 1063-85 (Washington: American Physiological Society, 1967).
It has been shown that the gastric mucous layer thickness typically varies from 5 to 200 xcexcm in the rat and 10 to 400 xcexcm in man. Occasionally, however, it can reach thicknesses as great as 1000 xcexcm in man, as described by Spiro, xe2x80x9cGlycoproteins,xe2x80x9d Annual Review of Biochemistry, 39:599-638 (1970); Labat-Robert and Decaeus, Pathologie et Biologie (Paris) 24:241 (1979); and Allen et al., xe2x80x9cMucus Glycoprotein Structure, Gel Formation and Gastrointestinal Mucus Functionxe2x80x9d in J. Nugent and M. O""Connor, Eds., Mucus and Mucosa, Ciba Foundation Symposium 109, Pitman, London, 1984, pp.137.
There is a need for methods for controlling or increasing the absorption of pharmaceutical agents from polymeric drug delivery devices such as polymeric microspheres through mucosal membranes. There also is a need for methods for delaying transit of the devices through nasal or gastrointestinal passages. It is therefore an object of the present invention to provide methods for improving the bioadhesive properties of polymeric drug delivery devices such as microspheres, tablets, capsules and stents. It is another object of the invention to provide methods for improving the adhesion of drug delivery devices such as microspheres to mucosal membranes including buccal and nasal membranes and membranes of the gastrointestinal and reproductive tracts. It is a further object of the invention to provide polymeric drug delivery devices with improved ability to bind to mucosal membranes which can be used to deliver a wide range of drugs or diagnostic agents in a wide variety of therapeutic applications.
Methods and compositions are provided for enhancing the bioadhesive properties of polymers used in drug delivery devices. The bioadhesive properties of a polymer are enhanced by incorporating a metal compound into the polymer to enhance the ability of the polymer to adhere to a tissue surface such as a mucosal membrane. Metal compounds which enhance the bioadhesive properties of a polymer preferably are water-insoluble metal compounds, such as water-insoluble metal oxides and hydroxides, including oxides of calcium, iron, copper and zinc. The metal compounds can be incorporated within a wide range of hydrophilic and hydrophobic polymers including proteins, polysaccharides and synthetic biocompatible polymers. In one embodiment, metal oxides can be incorporated within polymers used to form or coat drug delivery devices, such as microspheres, which contain a drug or diagnostic agent. The metal compounds can be provided in the form of a fine dispersion of particles on the surface of a polymer that coats or forms the devices, which enhances the ability of the devices to bind to mucosal membranes. The polymers, for example in the form of microspheres, have improved ability to adhere to mucosal membranes, and thus can be used to deliver a drug or diagnostic agent via any of a range of mucosal membrane surfaces including those of the gastrointestinal, respiratory, excretory and reproductive tracts.